Ross River virus (RRV) is the aetiological agent of epidemic polyarthritis (EPA) a predominantly rheumatic disease afflicting up to 5000 Australians annually. We show here for the first time that macrophages can be productively infected by RRV. Subneutralizing titres of anti-RRV IgG (but not IgM) also showed classical antibody-dependent enhancement (ADE) of RRV infection in macrophage and monocyte cell lines. No correlation between development of EPA and the preexistence of ADE titres was apparent, nor could sera raised against a related arbovirus, Barmah Forest, enhance RRV infection. Tumour necrosis factor-a, implicated in the immunopathogenesis of rheumatoid arthritis, was not secreted by RRV-infected monocytes or macrophages. Macrophage cell lines infected with RRV were, however, capable of producing virus for over 50 days. RRV-induced arthritis may therefore be due to the persistent productive infection of macrophages, perhaps established by a brief period of ADE early in infection.Ross River virus (RRV) is a mosquito-borne alphavirus endemic to Australia and New Guinea and is the aetiological agent of epidemic polyarthritis (EPA). In Australia, where EPA is a notifiable disease, up to 5000 cases are reported annually. In 1979/1980 an explosive epidemic also swept through several islands of the South Pacific resulting in tens of thousands of cases (Aaskov & Doherty, 1994). The principal symptom of EPA is arthritis/arthralgia, which is often severe and usually lasts for 30 to 40 weeks, with about 25 % of EPA patients experiencing symptoms for a year or more (Fraser, 1986). Approximately half of the EPA patients also experience a rash, fever, myalgia and/or lethargy. The current treatment with non-steroidal anti-inflammatory agents can provide relief, but it is often inadequate. EPA is rare in children and overall reports for the ratio of asymptomatic to symptomatic infections (resulting in EPA) range from 50:1 to approximately 2:1 (Aaskov & Doherty, 1994;Fraser, 1986).The rheumatic synovial exudates from EPA patients are largely devoid of neutrophils and contains a mononuclear cell infiltrate, predominantly composed of monocytes, vacuolated and phagocytic macrophages, T cells and B cells. RRV can be isolated from the peripheral * Author for correspondence. Fax +61 7 33620106. e-mail andreasS@qimr.edu.au blood and viral antigens can be detected in synovial monocyte/macrophages during the first week after the onset of symptoms (Fraser, 1986). Elevated interferon-7 (IFN-7) levels were also found in exudates taken during this time (J. R. E. Fraser & A. L. Cunningham, personal communication).RRV has a large host range and can infect many cell types (Aaskov & Doherty, 1994) including murine muscle cells, and human epidermal and synovial ceils (Seay et al., 1981 ;Fraser, 1986). Using the RRV prototype strain T48, we found that the following human cell types could be productively infected with RRV resulting in overt cytopathic effect (CPE): human primary dermal and synovial fibroblasts, primary endothelial cells,...